A large and growing body of evidence supports the hypothesis that vitamin D has antineoplastic effects in the colorectum and that vitamin D supplementation is a promising chemopreventive approach to reduce the burden of this disease. Supplementation is often required to increase levels of vitamin D because of insufficient dietary intake and sunlight exposure. However, it is not known how genetic factors may influence the response to supplementation with vitamin D. Interestingly, two recent genome wide association studies (GWAS) found that the circulating 25-hydroxyvitamin D level [25(OH)D], the best biomarker of vitamin D status, is influenced by variants at four loci that are located in or near genes coding for key proteins associated with vitamin D transport and metabolism: 1) the vitamin D binding protein (DBP), 2) the enzyme 7-dehydrocholesterol reductase (DHCR7), 3) the 25-hydroxylase enzyme CYP2R1, and 4) the 24-hydroxylase enzyme CYP24A1. It is not known whether these GWAS hits that influence 25(OH)D level also influence the increase in 25(OH)D that is achieved in response to vitamin D supplementation and, ultimately, the risk of colorectal neoplasia. We plan to begin to address this issue by investigating genetic effects on the response to supplementation in the current application and, subsequently, to investigate genetic effects on risk of colorectal neoplasia in future research. This work will be performed in an efficient and cost effective manner by utilizing the data and biospecimens from approximately 2,188 participants in an on-going NCI-funded randomized clinical trial of vitamin D3 (1000 IU/day) and calcium (1200 mg/day) supplementation for the prevention of colorectal adenomas: the Vitamin D/Calcium Polyp Prevention Study. DNA from these participants will be used to genotype the most statistically significant SNPs at each of the four loci associated with 25(OH)D levels in the GWAS analyses. Linear regression will be used to estimate the effect of these SNPs on the increase in 25(OH)D levels following one year of supplementation. In addition, we will explore whether other characteristics, such as body mass index and age, interact with these genetic variants in modifying the response to vitamin D supplementation. This research may identify individuals who are at risk for poor response to vitamin D supplementation and may be of clinical importance to understanding if individuals with different genotypic profiles require different doses of vitamin D. The public health significance of this work is substantial due to the prevalence of vitamin D insufficiency and the high incidence of colorectal cancer, osteoporosis, and other common diseases associated with poor vitamin D status.